Further encouraging results suggest that the nerve protein neurofilament light chain (NF-L) may be a reliable serum biomarker for detecting subclinical disease activity and treatment response in multiple sclerosis (MS).
Neurofilaments are neuron-specific cytoskeletal proteins that can be released following axonal damage. Elevated levels of these proteins have, therefore, been interpreted as reflecting axonal damage and neuronal death in MS and other neurologic conditions.
“Our patient cohort is quite unique in that they have so many MRI measurements available and we have shown that blood levels of NFL correlate very well with gadolinium-enhancing lesions on MRI,” lead investigator, Kristin N. Varhaug, MD, University of Bergen, Norway, told Medscape Medical News.
“These results suggest therefore that blood NF-L levels could be useful in apparently stable patients without clinical relapses to pick up disease activity. It may be possible to do this simple blood test instead of annual MRIs in the larger population and use the results to signal patients that need an MRI. Therefore, patients with stable clinical course and stable NF-L levels may be spared unnecessary, and costly, MRI scans, although this needs to be confirmed in larger prospective trials.”
The study was published online November 29 in Neurology Neuroimmunology and Neuroinflammation.
Indicator of Treatment Response
At study outset, all patients were treatment naive. At 6 months they received interferon β.
“Our results show that after starting treatment NF-L levels fell, so we also found a correlation with treatment response,” said Dr Varhaug.
However, the study did not show a relationship between blood NFL levels and relapse rate or disability progression. Dr Varhaug suggested this may have been because there were not enough patients with relapses or disability progression in this study.
“We probably need a larger population and longer follow-up time to see a correlation with relapse rate and disability. While we need to continue collecting data on NF-L from longer multicenter trials before any definite recommendations can be made, personally I feel that using this protein as a biomarker to monitor patients in conjunction with MRI is not an unreasonable thing to do,” she added.
The researchers also evaluated another protein — chitinase 3-like 1 (CHI3L1) — as a possible MS biomarker. This glycoprotein is upregulated in numerous chronic inflammatory conditions, and cerebrospinal fluid (CSF) levels have been correlated with MS disease progression.
But the current study did not show any correlation of serum levels of CHI3L1 to any clinical or MRI disease activity or interferon β-1a treatment.
“Our results suggest that CHI3L1 is not present in the blood in high enough concentrations to be a serum biomarker. It has been detected in relatively high levels in the CSF — but it may not cross the blood-brain barrier very well. Another possibility is that the ELISA [enzyme-linked immunosorbent assay] we used was not sensitive enough for CHI3L1,” said Dr Varhaug.
For the study, a cohort of 85 patients with relapsing-remitting MS was followed for 2 years (6 months without disease-modifying treatment and 18 months with interferon β-1a).
The Expanded Disability Status Scale was scored at baseline and every 6 months thereafter. MRI was performed at baseline and monthly for 9 months and then at months 12 and 24. Serum samples were collected at baseline and months 3, 6, 12, and 24.
The researchers analyzed serum levels of NF-L using a single-
molecule array assay and CHI3L1 by ELISA, and they estimated the association with clinical and MRI disease activity using mixed-effects models.
Results showed that both within-patient and between-patient variation in NF-L levels were independently associated with disease activity.
NF-L levels were significantly higher in patients with new T1 gadolinium-enhancing lesions (37.3 pg/mL) and new T2 lesions (37.3 pg/mL) compared with patients without such lesions (28.0 pg/mL and 27.7 pg/mL, respectively).
NF-L levels were associated with the presence of T1 gadolinium-enhanced lesions up to 2 months before and 1 month after the time of biomarker measurement. NF-L levels fell after initiation of interferon β-1a treatment (P < .001).
The researchers found that an increase of 10 pg/ml of NF-L in an individual was associated with a 48% increased risk for developing a new T1 lesion and a 62% increased risk for a new T2 lesion.
They note that although NF-L is present in much higher concentrations in the CSF than in the blood, “measurement of NF-L in serum appears sensitive enough to be taken into clinical use.”
A Note of Caution
In an accompanying editorial, Ruth Ann Marrie, MD, PhD, University of Manitoba, Winnipeg, Canada, called for some caution.
She acknowledges that “the ability to substitute a serum measure that could be assessed repeatedly for less frequent, less convenient, and more costly MRIs would be welcome.” However, she adds that “considerably more work is needed for serum NF-L levels to be appropriate for use in practice.”
“We need to establish that the associations reported apply to other MS populations, which differ with respect to their demographic (age, sex, and race) and clinical (disability, disease duration, clinical course, and comorbidities) characteristics and that the magnitude and direction of these associations are consistent.
“We also need to determine whether a 10-pg/mL change in NF-L levels for an individual with MS reproducibly indicates subclinical disease activity with adequate sensitivity and specificity, and whether reductions in those levels indicate resolution of activity for that individual. The lack of association between NF-L levels and clinical disease activity also needs to be addressed, hopefully by the use of larger cohorts,” she writes.
“Serum NF-L levels deserve continued evaluation as a biomarker of disease activity. However, several large, prospective cohort studies with comprehensively characterized and heterogeneous participants followed over longer periods are needed to determine whether it should be adopted in clinical practice,” Dr Marrie concludes.
The study was supported by The Kristian Gerhard Jebsen Foundation and the Torbjørg Hauges Legacy. Dr Varhaug has disclosed no relevant financial relationships. Dr Marrie serves on the editorial board of Neurology and Multiple Sclerosis Journal; receives research funding from the Canadian Institutes of Health Research, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, National Multiple Sclerosis Society, Crohn’s and Colitis Canada, Rx&D Health Research Foundation, and Waugh Family Chair in Multiple Sclerosis; and has conducted clinical trials funded by Sanofi-Aventis.
Neurol Neuroimmunol Neuroinflamm. Published online November 29, 2017. Abstract, Editorial
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